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Lymphocytic Leukemia Elias Jabbour M.D. 10-1-2018 Reasons for - PowerPoint PPT Presentation

Inotuzumab for Adult Acute Lymphocytic Leukemia Elias Jabbour M.D. 10-1-2018 Reasons for Recent Success in Adult ALL Rx Addition of TKIs to chemoRx in Ph-positive ALL Addition of rituximab to chemoRx in Burkitt and pre-B ALL


  1. Inotuzumab for Adult Acute Lymphocytic Leukemia Elias Jabbour M.D. 10-1-2018

  2. Reasons for Recent Success in Adult ALL Rx • Addition of TKIs to chemoRx in Ph-positive ALL • Addition of rituximab to chemoRx in Burkitt and pre-B ALL • Potential benefit of addition of CD19 antibody construct blinatumomab, and of CD22 monoclonal antibody inotuzumab to chemoRx in salvage and frontline ALL Rx

  3. Immuno-oncology in ALL • Antibodies, ADCs, immunotoxins, BiTEs, DARTs, CAR-T cells Bi-specific MoAb (CD19 & CD3) Jabbour E. Blood 125: 4010; 2015

  4. Historical Results in R/R ALL • Poor prognosis in R-R ALL Rx with standard of care (SOC) chemotherapy ≥2 prior One prior No prior salvage salvages Rate (95% CI) salvage (S1) (S2) (S3) 40 21 11 Rate of CR, % Median OS, 5.8 3.4 2.9 months Gökbuget N, et al. Haematologica . 2016;101:1524 – 33 .

  5. ALL Salvage Standards of Care in 2018 • Refer for investigational therapies-- MoAb + ChemoRx; CAR-T • Ph-positive ALL-- TKIs+ chemoRx; blinatumomab • Pre-B ALL-- – Blinatumomab (FDA approval 12.2014) – Inotuzumab (FDA approval 8.2017) – CART (FDA approval 8.2017) • T ALL: nelarabine • ChemoRx: FLAG IDA, Hyper CVAD, augmented HCVAD, MOAD

  6. Inotuzumab in ALL. 5 Mechanisms of Action • The antibody-antigen complex is rapidly internalized upon binding to CD22 • Calicheamicin is released inside the tumor cell - Calicheamicin is more potent than other cytotoxic chemotherapeutic agents • Calicheamicin binds to DNA, inducing double- stranded DNA breaks • Development of DNA breaks is followed by apoptosis of the tumor cell 5 Ricart. Clin Cancer Res. 2011; 17:6417 – 27

  7. Inotuzumab in ALL. Response Weekly, Response Monthly, Overall, N=40 No. (%) N=49 N=90 CR 9 (18) 8 (20) 17 (19) CRp 14 (29) 13 (32) 27 (30) CRi (marrow 5 (10) 3 ( 7) 8 (9) CR) Resistant 19 (39) 15 (37) 34 (38) Death < 4 wks 2 (4) 2 (5) 4 (4) OR 28 (57) 24 (59) 52 (58) • Median CRD 5-6 mos;Median survival 5-7.3 mos • Better results in S1-S2 Kantarjian, Cancer. 119: 2728-2736; 2013

  8. Inotuzumab Disposition & VOD Weekly Single dose (N=41) (N=49) BMT (N=14) BMT (N=22) MUD (N=5) MRD (N=6) MUD (N=14) MRD (N=7) Haplo (N=2) Cord (N=1) Cord (N=1) VOD (1/14) VOD (5/22) Conditioning Dual Alkylating Single Alkylating regimen (N=13) (N=21) VOD Cases 5 1 Kantarjian et al. Cancer. 2013; 119(15): 2728-36.

  9. Inotuzumab vs ChemoRx in R-R ALL. Design ● Open-label, phase 3 study; 326 pts randomized at 117 sites in 19 countries InO • Starting dose 1.8 mg/m 2 /cycle a • 0.8 mg/m 2 Day 1; 0.5 mg/m 2 Days 8 and 15 of a • R/R CD22+ ALL 1:1 Randomization 21 –28 Day cycle (≤6 cycles) (N=326) • Salvage 1 or 2 Standard of Care (SOC) Stratifications: • Ph – or Ph+ • Duration of 1st CR • FLAG or ≥12 vs <12 mo • Ara-C plus mitoxantrone or • Salvage 2 vs 1 • HIDAC • Aged ≥55 y vs <55 y • ≤4 cycles a InO dose reduced to 1.5 mg/m 2 /cycle once patient achieved CR/CRi. Kantarjian. NEJM. 375: 740; 2016 8

  10. Inotuzumab vs ChemoRx in R-R ALL (Phase 3 INOVATE Trial) Parameter INO Chemo Rx p value % CR/CRi 81 29 <.0001 % MRD negative 78 28 <0.0001 in CR Median OS 7.7 6.2 .01 (mos) Kantarjian. NEJM. 375: 740; 2016

  11. Overall Survival. 2-yr F/U 10 Kantarjian. Blood. 130: abst 1099; 2017

  12. VOD/SOS Among InO-Treated Pts ● VOD incidence: InO, 13% (n=22) vs SOC, 1% (n=1) ● 5 (3%) pts had VOD during study Rx (2 with pre-study SCT) ● 77/164 (47%) on InO had post-study SCT vs 33/162 (20%) in the SOC arm ─ 17/77 (22%) on InO had VOD post-SCT (5/17 also had pre-study SCT) ● Median (range) time to VOD after SCT: 15 (3 – 57) days MVA Analysis of Factors Associated With Post-SCT VOD Factor OR (95% CI) P value 7.6 (1.7 – 33.8) Alkylator conditioning (dual vs single) 0.008 Age (≥55 vs <55 y) 4.8 (1.0 – 22.0) 0.043 11 Kantarjian. NEJM. 375: 740; 2016

  13. Impact of MRD in R-R ALL Rx with INO 12 Jabbour. ASCO 2018: abst 7013

  14. Allo SCT Post Inotuzumab in R-R ALL No. Median OS, mo 24-Month Survival, % n Events (95% CI) (95% CI) 100 (A) All HSCT pts 101 58 9.2 (5.1, NE) 41.4 (31.5, 51.0) (B) 1st Allo-HSCT 86 46 11.8 (5.9, NE) 45.7 (34.7, 56.0) (C) Direct 1st Allo-HSCT 73 35 NE (8.5, NE) 51.1 (38.9, 62.1) 80 in CR/CRi Survival probability Censored 60 C B 40 A 20 0 0 5 10 15 20 25 30 35 Time (months) Kebriaei. Blood 130: abst 886; 2017

  15. MiniHCVD-INO in ALL. Design • Dose reduced HyperCVD for 8 courses – Cyclophosphamide (150 mg/m 2 x 6) 50% dose reduction – Dexamethasone (20 mg) 50% dose reduction – No anthracycline – Methotrexate (250 mg/m 2 ) 75% dose reduction – Cytarabine (0.5 g/m 2 x 4) 83% dose reduction • Inotuzumab on D3 (first 4 courses) • Rituximab D2 and D8 (first 4 courses) for CD20+ • IT chemotherapy days 2 and 8 (first 4 courses) • POMP maintenance for 3 years Jabbour. JAMA Oncology. 2018;4(2):230-234

  16. MiniHCVD-INO in ALL. Design Intensive phase 1 2 3 4 5 6 7 8 D3 D3 D3 D3 Maintenance phase 36 months MiniHCVD Mini-MTX-cytarabine POMP Maintenance Inotuzumab Inotuzumab First 6 pts 7 to 34 35 and beyond First cycle (mg/m 2 ) 1.3 1.8 1.3 C2-4 (mg/m 2 ) 0.8 1.3 1.0

  17. MiniHCVD-INO-Blina in ALL. Design • Dose reduced HyperCVD for 4-8 courses – Cyclophosphamide (150 mg/m 2 x 6) 50% dose reduction – Dexamethasone (20 mg) 50% dose reduction – No anthracycline – Methotrexate (250 mg/m 2 ) 75% dose reduction – Cytarabine (0.5 g/m 2 x 4) 83% dose reduction • Inotuzumab on D3 (first 4 courses) – Modified to 0.9 mg/m 2 C1 (0.6 and 0.3 on D1&8) and 0.6 mg/m 2 C2-4 (0.3 and 0.3 on D1&8) • Rituximab D2 and D8 (first 4 courses) for CD20+ • IT chemotherapy days 2 and 8 (first 4 courses) • Blinatumomab 4 courses and 3 courses during maintenance • POMP maintenance for 3 years, reduced to 1 year Jabbour. April 2018 update

  18. MiniHCVD-INO-Blina in ALL. Intensive Phase MiniHCVD 1 2 3 4 Mini-MTX-cytarabine Blinatumomab Consolidative Phase 5 6 7 8 POMP Maintenance Inotuzumab Total dose Dose per day Maintenance phase 4 8 12 C 1 (mg/m 2 ) 0.9 0.6 D2 & 0.3 D8 12 months C 2- 4 (mg/m 2 ) 0.6 0.3 D2 & D8

  19. MiniHCVD-INO-Blina in R/R ALL. (N=84) Characteristic Category No. (%) Age (yrs) Median [range] 35 [9-87] Gender Male 37 (44) Performance Status (ECOG) 2+ 16 (19) Salvage Status S1 53 (63) S1, Primary Ref 5 S1, CRD1<12m 22 S1, CRD1>12m 26 S2 16 (19) >S3 15 (18) Prior ASCT 19 (23) Karyotype Diploid 19 (23) T(4;11) 8 (10) Misc 44 (52) IM/ND 13 (15) CD22 Median [range] 96 [14-100] ≥ 20% CD20 19 (23)

  20. MiniHCVD-INO-Blina in R/R ALL. Response By Salvage (N=84) Response N (%) Salvage 1 49/53 92 S1, Primary refractory 5/5 100 S1, CRD1 < 12 mos 18/22 82 S1, CRD1 ≥ 12 mos 26/26 100 Salvage 2 9/16 56 ≥ Salvage 3 9/15 60 Overall 67/84 80 MRD negativity 51/64 80 Salvage 1 39/46 85 ≥ Salvage 2 12/18 67

  21. MiniHCVD-INO-Blina in R/R ALL. Survival • 3-yr CRD and OS rates 49% and 33%, respectively

  22. MiniHCVD-INO-Blina vs INO in R/R ALL. Survival

  23. MiniHCVD-INO-Blina in R/R ALL. Survival by Salvage 1 .0 T o ta l F a il 2 y O S M e d ia n S 1 5 3 % 2 5 m o s 4 8 2 2 S 2 1 6 1 3 1 1 % 6 m o s 0 .8 S 3 1 5 1 0 2 8 % 7 m o s F ra c tio n s u rv iv a l 0 .6 0 .4 0 .2 0 .0 0 1 2 2 4 3 6 4 8 6 0 M o n th s

  24. MiniHCVD-INO-/+Blina in ALL S1. Response (N=48) Response N (%) CR 35 73 CRp 8 17 CRi 1 2 ORR 44 92 MRD negativity at response 28/41 68 Overall 38/41 93 CCyR 19/21 90 No response 3 6 Early death 1 2 Jabbour. Cancer. 2018; In press

  25. INO + mini-HCVD +/- Blinatumomab in S1. Overall Survival / Progression-free Survival

  26. INO + mini-HCVD vs. Chemo in S1. PFS/OS with SCT Censoring OS PFS

  27. INO + mini-HCVD vs. INO monotherapy in S1. PFS/OS with SCT Censoring OS PFS

  28. Elderly ALL. Historical Results MDACC GMALL SEER Medicare N 122 268 1675 727 Median 15 NA 4 10 Survival (mos) OS (%) 20 (3-yr) 23 (5-yr) 13 (3-yr) NA O’Brien. Cancer 113: 2097, 2008; Gökbuget. Blood. 2013;122:1336; Li S. Blood. 2016;128:3981; Geyer. Blood 2017;129:1878

  29. MiniHCVD-INO in ALL. Response (N=58) Response N (%) CR 47 (87) CRp 5 (9) CRi 1 (2) ORR 53 (98) No response 1 (2) Early death 0 0 • Four patients were enrolled with CR Kantarjian. Lancet Oncology. 2018;19(2):240-248

  30. MiniHCVD-INO in ALL. Survival • Median follow up of 28 months (2-68) CRD & OS

  31. MiniHCVD-INO vs HCVAD in ALL.

  32. MiniHCVD-INO in ALL. VOD • Overall 14/135 (10%) – R-R 9/79: 9/61 (Single) vs 0/18 (weekly LD) – FL 5/57: 4/46 (Single) vs 1/11 (weekly LD)

  33. Inotuzumab + Bosutinib in R-R Ph- positive ALL or Lymphoid CML-BP • 16 pts (14 ALL; 2 CML-BP) Rx with inotuzumab 0.8-0.5-0.5mg/m 2 weekly then 1mg/m 2 Q4 wks; bosutinib 300-500 mg/D • 13/16 CR-CRi = 81%; 12/13 CGCR; 9/13 FCM-MRD negative; 8/13 (55%) PCR negative • Median EFS 8.8 mos; median OS 10.7 mos • 5/6 post allo SCT alive in CR Jain. Blood 130: abst 143; 2017

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